PROJECT SUMMARY The long-term goal of this project is to explore and validate the spiny mouse, Acomys, as a new and unique model system for understanding the molecular, cellular and tissue level mechanisms of reparative regeneration in mammals and to translate this knowledge to the development of novel concepts for therapeutic regeneration. Acomys can regenerate a staggering range of tissues in a scar-free manner after full thickness skin wounding: smooth muscle, skeletal muscle, dermis, hair, glands; additionally it can regenerate cartilage after ear punches; and uniformly displays little or no fibrosis during skeletal muscle regeneration, heart damage or spinal cord damage. We hypothesize that this lack of fibrotic reaction is a fundamental property of the cells of this organism because the genetic controls of collagen deposition and other matrix molecules have evolved differently to generate a weak-skinned phenotype which has major advantages to the survival of this species following prey attack. As a consequence, in response to damage the altered collagen fibrotic response permits endogenous regenerative mechanisms to come into play. The aims of this application are to generate a de novo whole genome sequence of Acomys so that we can perform comparative genomics to reveal the controls of collagen and matrix deposition either in coding or regulatory sequences following tissue damage. This work will enable the field to investigate the relation between fibrosis and regeneration and to generate an infrastructure from which to adapt and develop translational ideas for therapeutic regeneration in humans. RELEVANCE The ability to regenerate complex tissues and organs in a scar-free manner is the holy grail of regenerative medicine, but we currently have no mammalian model with which to investigate the cellular and molecular processes involved. We have discovered a new mammal, the spiny mouse, which can regenerate many tissues without inducing fibrosis and in this proposal we intend to uncover the genetic controls on regenerative mechanisms used by this organism for reparative regeneration, with huge implications for translational human endeavors.